Alzheimer's disease (AD) is a chronic progressive neurodegenerative disease associated with the presence of both amyloid beta peptide (A?) containing-plaques and neurofibrillary tangles (NFT) in the cortical region of brain tissue. In 2015, a new consensus criteria established by our group, in collaboration with a large group of prominent neuropathologists and neuroscientists, defined a new category of Alzheimer's disease (AD) neuropathologic changes termed primary age-related tauopathy (PART). Post-mortem neuropathological examination of individuals with PART reveals tissues lacking amyloid beta peptide (A?) containing-plaques, but still containing a number of AD-type NFTs. Patients with PART may have normal cognition, amnestic mild cognitive impairment (aMCI), or an amnestic dementia. The prevalence of PART dementia is unclear, with estimates ranging from 1-7%, but PART is likely more pervasive. Studies investigating the genetics and biochemical mechanisms of PART will have a profound impact in understanding the regional vulnerability of the temporal lobe and the broad pathogenesis of tauopathies. We hypothesize that subjects with PART have distinct characteristics that underlie their NFT+/A?- phenotype. In our first aim we will validate neuropathological criteria for PART and lay the groundwork for clinical and mechanistic studies that will elucidate disease burden, pathogenesis and progression. Brain tissue collected from dozens of domestic and international brain banks will be stained, imaged, and quantification of NFT burden will be performed using quantitative and semi-quantitative techniques as well as stereology. In the second aim we will test the hypothesis that PART has a genetic risk profile that overlaps with some aspects of AD genetics (e.g., MAPT haplotypes) but diverges with respect to others (e.g., APOE genotype). To accomplish this aim we will execute a genome wide association (GWA) study comparing frequency of known AD risk alleles in PART, AD and controls using DNA isolated from the tissue collected in aim one. Lastly, we will study and compare the onset and progression of PART using genetically manipulated iPSC cultures. This will explore the role PART-related genetics play in tauopathic disorders, and create a model cell line from iPSCs which will be used to further study how these genetic changes influence cell phenotype and genotype. In summary, the clinical-translational research performed in this study will establish PART as an A?-independent process with a unique neuropathological, biochemical, and genetic signature that distinguishes it from AD and other tauopathies.